Phase I and Pharmacokinetic Study of Intraoperative Intraperitoneal Heptaplatin in Patients with Surgically Resected Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Heptaplatin, a new platinum analog, has favorable toxicity profiles and antitumor activity, comparable to those of cisplatin, in the treatment of gastric cancer. This study was designed to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of heptaplatin administered by an intraperitoneal route in patients with resected advanced gastric cancer. MATERIALS AND METHODS: Seventeen patients with resected advanced gastric cancer were entered onto the study. After completion of a curative resection and an astomosis, heptaplatin was administered intraperiton eally in one liter of 5% dextrose solution. The starting heptaplatin dose was 400 mg/m2 of the body surface area, and was escalated in 200 mg/m2 increments, to cohorts of three patients. A pharmacokinetic analysis was carried out to determine the total and ultrafiltratable platinum concentrations in the plasma, peritoneal fluid, and urine. RESULTS: Patients were unable to tolerate a 1, 000 mg/m2 dose level, and at 800 mg/m2, reVersible Grade III toxic ities, including elevated creatinine, proteinuria, hypon- atremia, abdominal pain, and intraabdominal bleeding were noted. No significant toxicity was noted up to a 600 mg/m2 dose level. The ratio of the peak peritoneal to peak plasma drug concentrations were 19.4, 16.6 and 22.8 at doses of 400 mg/m2, 600 mg/m2 and 800 mg/m2, respectively. The pharmacological advantage, expressed as the peritoneal to plasma AUC ratio ranged from 4.3 to 7.0. CONCLUSION: Heptaplatin can be delivered by an intra peritoneal route, with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The MTD of intraperitoneal heptaplatin was 800 mg/m2. The major DLTs were nephrotoxicity and intraabdominal bleeding. The recommended starting dose for a subsequent study would be 600 mg/m2.

Allogeneic Peripheral Blood Stem Cell Transplantation in Hematological Malignancies: Stem Cell Mobilization with GM-CSF alone or a combination of GM-CSF and G-CSF from Normal Healthy Donors / 대한혈액학회지

BACKGROUND: Granulocyte-colony stimulating factor (G-CSF) has been used in normal heathy donors to mobilize hematopoietic progenitors. Recently, it was reported that an addition of granulocyte-macrophage-CSF (GM-CSF) mobilized more primitive CD34+ subsets than did G- CSF alone. We investigated the result of the allogeneic peripheral blood stem cell transplantation (PBSCT) with stem cells mobilized with GM-CSF alone or a combination of GM-CSF and G-CSF from normal healthy donors in hematological malignancies. METHODS: Twenty-nine patients with hematologic malignancies had allogeneic PBSCT from normal sibling donors. Nine healthy donors were mobilized with GM-CSF (Leucogen (R)) alone and 20 with a combination of GM-CSF and G-CSF (Leucostim (R)). After 5~8 days of cytokine treatment, PBSCs were collected by large volume leukapheresis and analyzed. RESULTS: Stem cells were collected from the HLA matched normal healthy sibling donors. The mean harvested cell content was 8.74+/-3.22X10(8) MNCs/kg, 15.65+/-16.02X10(6) CD34+ cells/kg of the patients. There were significant differences in the harvested MNC count between mobilization group with GM-CSF alone and group with a bination of GM-CSF and G-CSF. Observed side effects of cytokine mobilization were myalgia (76%), headache (41%), febrile sense (24%) and skin rash (10%). These complications disappeared within 48 hours after discontinuation of cytokines. The median interval to achieve a WBC count>500/uL was 15.00+/-4.23 days, and 14.00+/-33.01 days to a platelet count>20,000/uL. The actual incidence of acute GVHD was 36.4%, 22.7%, and 4.5% for skin, GIT, and liver, respectively. Immunosuppressant responsive chronic GVHD developed in 63.1% (12/19) of assessable patients including 6 cases who had donor lymphocyte infusions. CONCLUSION: In this study, GM-CSF based cytokine mobilization was able to collect sufficient numbers of stem cells and allow rapid engraftment in the allogeneic PBSCT. Mobilization protocol with a combination of GM-CSF and G-CSF seemed to be superior to GM-CSF alone. Acute GVHD in patients with allogeneic PBSCT didn't appear to be more severe than in patients undergoing allogeneic BMT.

Allogeneic Peripheral Blood Stem Cell Transplantation with Stepwise Donor Lymphocyte Infusions in Mantle Cell Lymphoma Relapsed after Autologous PBSCT / 대한혈액학회지

Mantle cell lymphoma (MCL) is a distinctive clinicopathologic entity and represents 5~10% of all non-Hodgkin's Lymphoma (NHL). The median survival of patients with MCL is only 3 years, and none of the available conventional chemotherapy regimens appear curative. Encouraging results have been reported with high dose chemotherapy with stem cell transplantation for its treatment. Particularly, alloSCT appears to induce durable remission via graft-versus-lymphoma (GVL) effect. Donor lymphocyte infusions (DLIs), by virtue of graft-versus-tumor effect, have been shown to induce remissions in leukemia that recurs after alloSCT. But GVL effect of DLI has not been clearly established in NHL. We describe a patient with relapsed MCL shortly after high dose chemotherapy with autoSCT who was successfully treated with alloPBSCT. The patient presented with diffuse GI and spleeninvolvement at the time of alloPBSCT. The patient received Bu/Cy/VP-16 as preparative regimen followed by alloPBSCT. The patient received cyclosporin and methotrexate as GVHD prophylaxis. Prednisone was added after grade II GVHD. The patient had partial response by D+64. To enhance GVL effect, the patient received G-CSF primed DLI serially at D+64 and D+92. Grade IV GVHD developed 19 days after 2nd DLI and was partially controlled with a combination of cyclosporin, prednisone and mycophenolate mofetil. Clinical complete remission was observed at D+112, and maintained till last follow-up day (D+515). Our findings suggest that alloSCT and stepwise DLIs may offer a curative approach to MCL.

The Frequency and Clinical Significance of Multidrug Resistance-1 (MDR-1) Gene Expression in Acute Myeloid Leukemia / 대한혈액학회지

BACKGROUND: The expression of the multidrug resistance-1 (MDR-1) gene which encodes p-glycoprotein, is recognized as a biological mechanism possibly contributing to treatment failure in patients with acute myeloid leukemia (AML). Recent studies indicate its association with poor risk factors such as cytogenetic pattern and surface phenotype of blasts. We analyzed the role of MDR-1 gene expression in 36 chemo-naive AML patients. METHODS: In 36 patients, clinical data were reviewed and compared to MDR-1 gene expression, immunophenotyping results on CD7 & CD34, cytogenetic pattern and other suggestive prognostic factors. RESULTS: Median follow-up period was 150 days. The MDR-1 gene expression was observed in 19 out of 36 patients (52.8%). Significant correlation between MDR-1 gene and CD7 & CD34 expression was found. Sixteen out of 17 (94.1%) MDR-1 negative patients harbored favorable cytogenetic patterns, where as 11 out of 19 (57.9%) MDR-1 positive patients had favorable cytogenetic patterns. MDR-1 gene expression was not correlated to disease free survival (DFS), nor overall survival (OS) statistically although it has shown significant correlation to complete remission (CR) rate (P =0.001). CONCLUSION: We found that lack of MDR-1 gene expression was exclusively associated to favorable cytogenetic patterns in our study. In order to clarify the relationship between the role of MDR-1 gene and clinical outcome or other prognostic features, including cytogenetic pattern, further larger studies would be necessary.

An ALL Case with Trichosporon beigelii Pneumonia Developed during Severe Pancytopenic Period after Salvage Chemotherapy / 대한혈액학회지

Trichosporon beigelii belongs to the family of Cryptococcaceae. T. beigelii is a rare causative agent of invasive pneumonia in immunocompromised patients. T. beigelii pneumonia is characterized by persistent fever unresponsive to broad-spectrum antibiotic the- rapy, coughing with bloody sputum, and rapidly progressive dyspnea. Its diagnosis should be based on clinical suspicion and confirmed by culture and histologic examination of biopsy tissue. We describe an ALL patient with T. beigelii pneumonia developed during severe pancytopenic period after salvage chemotherapy.

Mantle cell lymphoma presented as multiple lymphomatous polyposis: clinical review of 4 cases / 대한내과학회지

Multiple lymphomatous polyposis(MLP) is an interesting clinical entity of non-Hodgkin's lymphoma(NHL) and is defined as B-cell lymphoma characterized by the presence of multiple lymphomatous polyps along the gastrointestinal tract. Recently MLP has been considered as a variant form of mantle cell lymphoma(MCL). The median survival of patients with MCL is only 3 years, and none of the available conventional chemotherapy regimens appears curative. Encouraging results have been reported with high dose chemotherapy with autoSCT and alloSCT for its treatment. We introduce 4 cases of MLP diagnosed as MCL by morphologic and immunologic method. The common clinical findings of these cases were splenomegaly (4/4), multiple intraabdominal lymphadenopathy (4/4), and advanced stage (3/4) at presentation. The overall remission duration was relatively short (5-27 months) and three of four cases relapsed after conventional chemotherapy or autologous stem cell transplant. Our report suggests that MCL presented as MLP is a high risk subgroup of NHL and more aggressive approach may be needed for cure.

Erythrocyte Depletion Effect of Compression Method with 6% Hydroxyethyl Starch in Human Umbilical Cord Blood / 대한수혈학회지

BACKGROUND: Stem cell transplantation with high dose chemoradiotherapy has made it possible to cure a significant proportion of patients with hematopoietic malignancies. RBC purging is an essential step prior to transplantation in ABO mismatched setting. The purpose of this study is to develop a new simple method for RBC depletion from harvested stem cells. METHODS: Ten cord bloods were collected during deliveries at Kyungpook National University Hospital, Taegu, Korea at August, 1998. All nucleated cells were collected after the compression of bags with 6% hydroxyethyl starch and cord blood for 4 hours. The cell viability of mononucleated cell (MNC) was calculated after 24~72 hours. RESLUTS: The collected mean volume of cord blood was 37.1 +/- 6.7 ml. The WBC count was 10,852 +/- 1,137/microL. The 3.90 +/- 0.62x108 TNC and 1.82 +/- 0.36x108 MNC were obtained per collection. TNC efficiency was 83.8 +/- 7.01% and MNC efficiency was 90.9 +/- 9.23% by compression method with 6% hydroxyethyl starch. RBC contamination was negligible. The cell viabilities of mononuclear cell were kept in a range of 99~100% after 24~72 hours. CONCLUSION: Because compression method with 6% hydroxyethyl starch progresses in closed system is simple & easy, has high erythrocyte depletion efficacy, and can maintain high viability of stem cells, it can be used for RBC purging in ABO mismatched stem cell transplantation.